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Inotuzumab ozogamicin

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Inotuzumab ozogamicin
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD22
Clinical data
Trade namesBesponsa
Other namesCMC-544
AHFS/Drugs.comMonograph
MedlinePlusa617041
License data
Pregnancy
category
  • AU: D
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding97% (cytotoxic agent)
Elimination half-life12.3 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6518H10002N1738O2036S42
Molar mass146634.36 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Inotuzumab ozogamicin, sold under the brand name Besponsa, is an antibody-drug conjugate medication used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia.[4][5] It is administered by intravenous infusion.[4][5]

The medication consists of a humanized monoclonal antibody against CD22 (inotuzumab), linked to a cytotoxic agent from the class of calicheamicins called ozogamicin.[6]

The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[7]

Medical use

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Inotuzumab ozogamicin is used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia.[4][5]

In March 2024, the FDA approved inotuzumab ozogamicin for the treatment of children aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.[8]

Adverse effects

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The FDA label for the use of inotuzumab ozagamicin carries a boxed warning concerning the risk of liver toxicity, in particular hepatic veno-occlusive disease (VOD), which has been fatal in some people.[9] The risk of this is higher in people who take the drug before having hematopoietic stem cell transplantation (HSCT) and more people die who have HSCT following treatment with this drug, than people who have HSCT, taking other chemotherapies. The risk gets higher as more rounds of treatment with inotuzumab ozogamicin are administered.[5]

The most common serious adverse reactions in people taking the drug in the clinical trial leading to approval were infections (23%), loss of neutrophils with fever (11%), hemorrhage (5%), stomach pain (3%), fever (3%), VOD (2%), and tiredness (2%).[4]

More than 20% of people had the following adverse reactions: loss of platelets (51%), loss of neutrophils (49%), infections (48%), anemia (36%), leukopenia (35%), tiredness (35%), hemorrhage (33%), fever (32%), nausea (31%), headache (28%), loss of neutrophils with fever (26%), elevated transaminases (26%), stomach pain (23%), and jaundice (21%).[citation needed]

Between 10% and 20% of people also had loss of appetite, vomiting, diarrhea, mouth sores, constipation, chills, and injection site reactions.[4]

In studies in pregnant animals, the drug caused harm to the fetus at doses less than those used clinically, and so the drug has not been tested in pregnant women.[4]

Pharmacology

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The antibody component of inotuzumab ozogamicin binds to CD22 receptors, which are expressed mostly on B cells. The whole conjugate is then drawn into the cell, where the ozogamicin is cleaved from the antibody by the acidic environment of the lysosome.[10] The ozogamicin eventually travels to the nucleus where it breaks up DNA, causing the cell to die.[4]

Chemistry

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Inotuzumab ozogamicin consists of the humanized monoclonal antibody inotuzumab (against CD22), linked to a cytotoxic agent from the class of calicheamicins called ozogamicin.[6][11] Ozogamicin is N-acetyl-gamma-calicheamicin dimethylhydrazide.[4] It includes the same linker, called "AcBut", and toxin, as gemtuzumab ozogamicin, which arose from the same collaboration.[12] The linker is a carbonyl-containing carboxylic acid.[13] The antibody, originally called G5/44, was created by grafting the complementarity-determining regions and some framework residues from the murine anti-CD22 mAb m5/44, onto human acceptor frameworks.[14]

History

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Inotuzumab ozogamicin was discovered by scientists collaborating at Celltech and Wyeth, and it was developed by Pfizer which had acquired Wyeth. Celltech and Wyeth entered into a collaboration in 1991 to develop antibody-drug conjugates.[15]

The humanized antibody portion was generated at Celltech and the DNA encoding it was transfected into CHO cells, which were sent to Wyeth, where chemists expressed and purified the antibodies and conjugated them with the linker to the cytotoxin; the work was published in 2004.[14] Celltech was acquired by UCB in 2004[16] and Wyeth was acquired by Pfizer in 2009.[17]

In May 2013, a phase III trial in patients with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma (NHL) who were not candidates for intensive high-dose chemotherapy was terminated for futility.[18]

In March 2024, the FDA approved inotuzumab ozogamicin for the treatment of children aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.[8] Efficacy was evaluated in a multicenter, single-arm, open-label study in 53 pediatric participants aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.[8] Two dose levels were evaluated--an initial dose of 1.4 mg/m2/cycle in 12 participants and 1.8 mg/m2/cycle in 41 participants.[8] Premedications included methylprednisolone 1 mg/kg (maximum of 50 mg), an antipyretic, and an antihistamine.[8] Participants received a median of 2 cycles of therapy (range: 1 to 4 cycles).[8] The application was granted priority review and orphan drug designations.[8]

Society and culture

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In 2017, inotuzumab ozogamicin was approved by the European Commission and the FDA for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia under the brand name Besponsa (Pfizer/Wyeth).[4][5]

References

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  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ "Regulatory Decision Summary for Besponsa". 23 October 2014.
  3. ^ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.
  4. ^ a b c d e f g h i j "Besponsa 1 mg powder for concentrate for solution for infusion". UK Electronic Medicines Compendium. June 2017. Retrieved 19 August 2017.
  5. ^ a b c d e f "Besponsa- inotuzumab ozogamicin injection, powder, lyophilized, for solution". DailyMed. 15 September 2020. Retrieved 16 November 2020.
  6. ^ a b Ricart AD (October 2011). "Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin". Clinical Cancer Research. 17 (20): 6417–6427. doi:10.1158/1078-0432.ccr-11-0486. PMID 22003069.
  7. ^ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  8. ^ a b c d e f g "FDA approves inotuzumab ozogamicin for pediatric patients with acute lymphoblastic leukemia". U.S. Food and Drug Administration. 6 March 2024. Retrieved 9 March 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  9. ^ Yang X (13 May 2020). "Inotuzumab Ozogamicin is an Effective Salvage Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with High- Risk Molecular Features, Including Tp53 Loss". doi:10.26226/morressier.5ebc261fffea6f735881a254. S2CID 242875059. Retrieved 21 August 2023.
  10. ^ "Inotuzumab ozogamicin (CMC-544)". ADC Review. 20 February 2016.
  11. ^ "Recommended INN: List 54" (PDF). WHO Drug Information. 19 (3). 2005.
  12. ^ Damle NK, Frost P (August 2003). "Antibody-targeted chemotherapy with immunoconjugates of calicheamicin". Current Opinion in Pharmacology. 3 (4): 386–390. doi:10.1016/S1471-4892(03)00083-3. PMID 12901947.
  13. ^ Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, et al. (2002). "Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia". Bioconjugate Chemistry. 13 (1): 47–58. doi:10.1021/bc010021y. PMID 11792178.
  14. ^ a b DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, et al. (March 2004). "Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies". Blood. 103 (5): 1807–1814. doi:10.1182/blood-2003-07-2466. PMID 14615373.
  15. ^ "Inotuzumab Ozogamicin". Informa Biomedtracker. Archived from the original on 19 August 2017. Retrieved 19 August 2017.
  16. ^ "Celltech sold to Belgian firm in £1.5bn deal". The Guardian. 18 May 2004.
  17. ^ Sorkin AR, Wilson D (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times.
  18. ^ "Pfizer Discontinues Phase 3 Study of Inotuzumab Ozogamicin in Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma (NHL) Due to Futility. May 2013". Archived from the original on 8 August 2014. Retrieved 20 July 2014.
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